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1.  Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy 
PLoS ONE  2014;9(1):e85031.
Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.
doi:10.1371/journal.pone.0085031
PMCID: PMC3885684  PMID: 24416337
2.  LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by the DYT1 Dystonia Mutation 
Molecular Biology of the Cell  2009;20(11):2661-2672.
TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.
doi:10.1091/mbc.E09-01-0094
PMCID: PMC2688546  PMID: 19339278
3.  Ophthalmological morbidity in very-low-birthweight infants with bronchopulmonary dysplasia. 
This study was undertaken to determine the relationship between retinopathy of prematurity, ocular sequelae of retinopathy, and bronchopulmonary dysplasia in infants weighing < 1250 g at birth prior to the introduction of steroid therapy for chronic lung disease. Ophthalmological data from 67 infants (22 with severe bronchopulmonary dysplasia and 45 controls) who were enrolled prospectively in an early intervention program were analyzed. The infants had two or more eye examinations prior to discharge and a follow-up examination at 12 to 18 months postconceptual age. The incidence of any retinopathy of prematurity was 33%, and severe retinopathy was 25%. Infants with severe bronchopulmonary dysplasia were 1.7 times more likely to develop any retinopathy and 1.8 times more likely to develop severe retinopathy than controls. The incidence of ocular sequelae, was 45%. Infants with any retinopathy had a 2.3 odds of developing sequelae, and infants with severe retinopathy had a 2.64 odds ratio. When adjusted for bronchopulmonary dysplasia, the odds ratio for developing sequelae was 1.36 in infants with any retinopathy and 1.27 in those with severe retinopathy. The predictors of retinopathy were lower birthweight and gestational age, acidosis, and hypoxemia. Bronchopulmonary dysplasia per se has an adverse effect on ophthalmologic morbidity. Evaluation of the adverse effect of any therapy for chronic lung disease on retinopathy of prematurity should make adjustments for the underlying lung disease.
PMCID: PMC2608256  PMID: 9347682
4.  Genetic susceptibility to retinopathy of prematurity: the evidence from clinical and experimental animal studies 
The British Journal of Ophthalmology  2007;91(12):1704-1708.
Despite advances in management and treatment, retinopathy of prematurity remains a major cause of childhood blindness. Evidence for a genetic basis for susceptibility to retinopathy of prematurity is examined, including the influences of sex, ethnicity, and ocular pigmentation. The role of polymorphisms is explored in the genes for vascular endothelial growth factor and insulin‐like growth factor‐1, and of mutations in the Norrie disease gene. Insights into the genetic basis of retinopathy of prematurity provided by the animal model of oxygen induced retinopathy are examined. Evidence for a genetic component for susceptibility to retinopathy of prematurity is strong, although the molecular identity of the gene or genes involved remains uncertain.
doi:10.1136/bjo.2007.117283
PMCID: PMC2095497  PMID: 18024814
retinopathy of prematurity; oxygen induced retinopathy; angiogenesis; genetic risk factors; molecular genetics
5.  Systematic Review of Digital Imaging Screening Strategies for Retinopathy of Prematurity 
Pediatrics  2008;122(4):825-830.
BACKGROUND
Retinal imaging with remote interpretation could decrease the number of diagnostic eye examinations that premature infants need for the detection of retinopathy of prematurity and thus decrease the time demand on the relatively small pool of ophthalmologists who perform retinopathy of prematurity examinations.
OBJECTIVE
Our goal was to review systematically the evidence regarding the reliability, validity, safety, costs, and benefits of retinal imaging to screen infants who are at risk for retinopathy of prematurity.
METHODS
We searched Medline, the Cochrane library, CINAHL, and the bibliographies of all relevant articles. All English-language studies regardless of design with primary data about our study questions were included. We excluded (1) studies that only included subjects with retinopathy of prematurity, (2) hypothetical models other than cost-effectiveness studies, and (3) validity studies without sufficient data to determine prevalence, sensitivity, and specificity or that only evaluated subjects for 1 component of retinopathy of prematurity (eg, plus disease only).
RESULTS
Studies of only 1 retinal imaging device (RetCam [Clarity Medical Systems, Inc, Pleasanton, CA]) met the inclusion criteria. There was a wide range in reported sensitivity, but specificity was high. There were several important limitations noted, including the eye as the unit of analysis instead of the individual or variations in the criteria for determining a true-positive or true-negative screening result. The risk of retinal hemorrhage resulting from imaging is low, and systemic effects (eg, bradycardia, hypertension, decreased oxygen saturation) are mild. No generalizable cost-effectiveness data were found.
CONCLUSIONS
The evidence base is not sufficient to recommend that retinal imaging be routinely adopted by NICUs to identify infants who have serious retinopathy of prematurity.
doi:10.1542/peds.2007-3667
PMCID: PMC2572706  PMID: 18829807
retinopathy of prematurity; photography; image interpretation; telemedicine; evidence-based medicine; review
6.  Retinal Degenerative and Hypoxic Ischemic Disease 
A broad spectrum of retinal diseases affects both the retinal vasculature and the neural retina, including photoreceptor and postreceptor layers. The accepted clinical hallmarks of acute retinopathy of prematurity (ROP) are dilation and tortuosity of the retinal vasculature. Additionally, significant early and persistent effects on photoreceptor and postreceptor neural structures and function are demonstrated in ROP. In this paper, we focus on the results of longitudinal studies of electroretinographic (ERG) and vascular features in rats with induced retinopathies that model the gamut of human ROP, mild to severe. Two potential targets for pharmaceutical interventions emerge from the observations. The first target is immature photoreceptors because the status of the photoreceptors at an early age predicts later vascular outcome; this approach is appealing as it holds promise to prevent ROP. The second target is the interplay of the neural and vascular retinal networks, which develop cooperatively. Beneficial pharmaceutical interventions may be measured in improved visual outcome as well as lessening of the vascular abnormalities.
doi:10.1007/s10633-008-9127-8
PMCID: PMC2629502  PMID: 18483822
7.  Ocular Neovascularization 
Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal vascular diseases, in which there is leakage and/or neovascularization (NV) from retinal vessels, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Retinal hypoxia is a key feature of the first category of diseases resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), placental growth factor, stromal-derived growth factor-1 and their receptors as well as other hypoxia-regulated gene products such as angiopoietin-2. Although hypoxia has not been demonstrated as part of the second category of diseases, HIF-1 is elevated and thus the same group of hypoxia-regulated gene products plays a role. Clinical trials have shown that VEGF antagonists provide major benefits for patients with subretinal NV due to AMD and even greater benefits are seen by combining antagonists of VEGF and PDGF-B. It is likely that addition of antagonists of other agents listed above will be tested in the future. Other appealing strategies are to directly target HIF-1 or to use gene transfer to express endogenous or engineered anti-angiogenic proteins. While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases.
doi:10.1007/s00109-013-0993-5
PMCID: PMC3584193  PMID: 23329331
Angiogenesis; age-related macular degeneration; diabetic retinopathy; hypoxia-inducible factor-1; vascular endothelial growth factor; platelet-derived growth factor
8.  Propranolol Inhibition of β-Adrenergic Receptor Does Not Suppress Pathologic Neovascularization in Oxygen-Induced Retinopathy 
Purpose.
Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects.
Methods.
Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups.
Results.
None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor.
Conclusions.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
doi:10.1167/iovs.12-9691
PMCID: PMC3376075  PMID: 22491401
9.  Clinical factors associated with retinopathy of prematurity. 
Archives of Disease in Childhood  1988;63(5):522-527.
In the period from September 1983 until June 1986 a prospective study was carried out to determine the incidence and severity of retinopathy of prematurity in inborn infants of less than 1500 g at birth and the risk factors associated with the development of retinopathy of prematurity in infants of less than 31 weeks' gestation. One hundred and forty four infants were eligible for inclusion in the study. Altogether 140 infants of less than 1500 g birth weight were examined, 42 (30%) of whom developed retinopathy of prematurity. Fifteen of these infants had progression to advanced disease (stage III or stage IV). One hundred and seventeen of the infants were of less than 31 weeks' gestation and 34 (29%) of them developed retinopathy of prematurity. Thirty four risk factors shown previously to be associated with the development of the disease were collected prospectively and analysed using multiple logistic regression analysis to determine the independently significant variables. Three risk factors: acidosis, the number of times that the pH was less than 7.2; hyperoxia, the number of times that arterial oxygen tension was greater than 12 kPa; and gestational age were found to be independently associated with the development of retinopathy of prematurity in these infants. These findings suggest that acidosis may be an important aetiological factor in the pathogenesis of this disease.
PMCID: PMC1778913  PMID: 3389868
10.  Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity 
The New England journal of medicine  2011;364(7):603-615.
BACKGROUND
Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity.
METHODS
We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks’ postmenstrual age.
RESULTS
We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks’ postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P = 0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P = 0.003) but not for zone II disease (P = 0.27).
CONCLUSIONS
Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety.
doi:10.1056/NEJMoa1007374
PMCID: PMC3119530  PMID: 21323540
11.  Combination of Intravitreal Ranibizumab and Laser Photocoagulation for Aggressive Posterior Retinopathy of Prematurity 
Case Reports in Ophthalmology  2012;3(1):136-141.
Purpose
To report on 2 cases of aggressive posterior retinopathy of prematurity (ROP) treated with intravitreal ranibizumab (Lucentis®) and laser photocoagulation.
Methods
Two premature females, born at 25 and 26 weeks’ gestation with a birth weight of 530 and 550 g, respectively, with aggressive posterior ROP received combined treatment with laser photocoagulation and intravitreal ranibizumab (0.3 mg [30 µl]) to each eye. Structural outcomes were evaluated by indirect ophthalmoscopy and documented by retinography.
Results
An intravitreal injection was made at 34 weeks of postmenstrual age in the first case, followed by laser photocoagulation 1 week later. There was a partial regression of ROP with treatment. Five weeks later, neovascularization regrowth with bleeding in both eyes (intraretinal and subhyaloid) occurred and retreatment with combined therapy was performed. In the second case, single therapy with laser photocoagulation was made at 34 weeks of postmenstrual age. In spite of the confluent photocoagulation in the avascular area, progression to 4A ROP stage occurred 1 week later. Both eyes were retreated 1 week later with intravitreal ranibizumab and laser photocoagulation. Treatment resulted in ROP regression in both cases. There were no signs of systemic or ocular adverse side effects.
Conclusion
The cases presented show that combination therapy of indirect laser photocoagulation and intravitreal ranibizumab can be effective in the management of aggressive posterior ROP. Further investigation on anti-VEGF safety in premature infants is necessary. Additional studies are needed to define the role of anti-VEGF in ROP treatment.
doi:10.1159/000338623
PMCID: PMC3362187  PMID: 22649347
Retinopathy of prematurity; Laser photocoagulation; Ranibizumab; Anti-VEGF therapy
12.  Diode laser treatment for retinopathy of prematurity: structural and functional outcome. 
AIMS--The anatomical and functional outcome of 13 babies with retinopathy of prematurity (ROP) treated with binocular indirect ophthalmoscope diode laser photocoagulation was assessed. METHODS--Thirteen babies (25 eyes) at median postmenstrual age (PMA) 25.5 weeks and median birth weight 725 g were treated with binocular indirect ophthalmoscope (BIO) diode laser photocoagulation when threshold retinopathy of prematurity (ROP) was detected at median PMA 35 weeks. Retinopathy was more severe in the nasal retina in 15 eyes. The median severity of retinopathy was 6 clock hours grade 3 disease. All babies were treated under general anaesthetic with no significant ocular or systemic complications during treatment. The median number of burns was 1200. RESULTS--Resolution of active retinopathy occurred 1-2 weeks following treatment in all but one baby. All eyes had favourable anatomical and functional outcome as defined by the Cryo-ROP study group at a median age of 19.5 months of follow up. CONCLUSION--BIO diode laser treatment is as effective as cryotherapy with less morbidity.
PMCID: PMC505188  PMID: 7662625
13.  Retinopathy of prematurity: age at onset. 
Archives of Disease in Childhood  1986;61(8):774-778.
The age at which retinopathy of prematurity was first seen was determined in 143 infants. In all, the initial ophthalmological examination was normal. Birth weights varied from 630 to 2700 g and gestational ages from 24.5 to 40.0 weeks. The median postnatal age at which acute retinopathy of prematurity was first seen was 51 and 40 days for those less than 28 and greater than or equal to 28 weeks' gestational age, respectively, and this difference is highly significant. Similar results were obtained when infants were grouped according to birth weight less than 1000 or greater than or equal to 1000 g. Using postmenstrual age as the variable, the first signs of retinopathy of prematurity were seen over a fairly narrow age range and 86% of infants developed retinopathy between 32.5 and 38.5 weeks of age. These findings suggest that the age (but not the occurrence or severity) at which retinopathy of prematurity is first seen is controlled predominantly by stage of development rather than neonatal events.
PMCID: PMC1777954  PMID: 3755580
14.  Regionalisation of retinopathy of prematurity (ROP) screening improves compliance with guidelines: an audit of ROP screening in the Northern Region of England 
AIMS—This project was designed to determine whether a coordinated regional strategy can improve the implementation of national guidelines for screening for retinopathy of prematurity (ROP), and to identify causes for failure of compliance.
METHODS—Retrospective case note audit relating to two periods, 1990-1 and 1994, involving all 17 neonatal intensive care units in the Northern Region of England. Between the two periods, a regional strategy was instituted in an endeavour to improve compliance. Babies born in or admitted to the units during the study periods who were eligible for ROP screening were included. Screening performance was assessed against a standard of 100% compliance with the guidelines. In the second audit period compliance with subsidiary standards was also measured, and reasons for failure were identified.
RESULTS—Compliance improved from 47% (262/558) in the first audit cycle to 73% (264/360) in the second. Subgroup analysis in this second cycle indicated better compliance (93.3%) in higher risk babies (⩽ 29 weeks' gestational age). Babies transferred between units, discharged home before screening, or who failed to qualify for screening on one of the two defined criteria, were more likely to be missed.
CONCLUSION—A carefully implemented regional approach to screening resulted in a higher uptake for babies most at risk. Simple recommendations are made to achieve further improvement in compliance with the guidelines. The wider implications for screening in other conditions and in other areas and specialties are highlighted.


doi:10.1136/bjo.85.7.807
PMCID: PMC1724044  PMID: 11423454
15.  The blinding mechanisms of incontinentia pigmenti. 
Five case histories illustrate the disabling visual diseases caused by retinal and cerebral infarction in incontinentia pigmenti. Cortical blindness was definitely present in one baby, who had bilateral absence of light perception, and was probably present in a second infant also. Retinal detachment occurred in three eyes of three patients, one of whom had spontaneous reattachment. In a second patient, a partial tractional retinal detachment progressed within 4 months during infancy to a total, inoperable, retrolental, white fibrovascular mass mimicking stage 5 retinopathy of prematurity. Phthisis bulbi resulted. In a third patient, a localized tractional retinal detachment originated at the nonperfused macula and extended over a 7-month period to the ora serrata. Preretinal neovascularization waxed and waned in these and other patients. Abnormalities of the macula were pronounced but were sometimes difficult to detect. Their severity and relative frequency have not been previously described in detail. Abnormalities included blunting or absence of the foveal pit and absence of the normal foveal avascular zone. One patient at 12 days of age had an infarcted macula with a cherry-red spot. Similar episodes may have occurred in other children and would be sufficient to explain the appearance of macular abnormalities and otherwise unexplainable poor visual acuity in older individuals. Well-focused macular angiography appears to be highly useful in explaining visual disability due to abnormal foveal anatomy and function. Optic atrophy occurred in several eyes. Its pathogenesis may be multifactorial. Further research is necessary to elucidate the mechanisms of vascular closure in the retina as well as the pathogenesis of destructive encephalopathy in this exceptionally severe disease. Valid therapeutic possibilities may then become more obvious than they are at present. It is possible that the retina and brain undergo similar disease processes in incontinentia pigmenti.
Images
PMCID: PMC1298505  PMID: 7886862
16.  Blockade of VEGFR1 and 2 Suppresses Pathological Angiogenesis and Vascular Leakage in the Eye 
PLoS ONE  2011;6(6):e21411.
Objective
VEGFR1 and 2 signaling have both been increasingly shown to mediate complications of ischemic retinopathies, including retinopathy of prematurity (ROP), age-related macular degeneration (AMD), and diabetic retinopathy (DR). This study evaluates the effects of blocking VEGFR1 and 2 on pathological angiogenesis and vascular leakage in ischemic retinopathy in a model of ROP and in choroidal neovascularization (CNV) in a model of AMD.
Materials and Methods
Neutralizing antibodies specific for mouse VEGFR1 (MF1) and VEGFR2 (DC101) were administrated systemically. CNV was induced by laser photocoagulation and assessed 14d after laser treatment. Retinal NV was generated in oxygen-induced ischemic retinopathy (OIR) and assessed at p17. NV quantification was determined by measuring NV tufts and vascular leakage was quantified by measuring [3H]-mannitol leakage from blood vessels into the retina. Gene expression was measured by real-time quantitative (Q)PCR.
Results
VEGFR1 and VEGFR2 expressions were up-regulated during CNV pathogenesis. Both MF1 and DC101 significantly suppressed CNV at 50 mg/kg: DC101 suppressed CNV by 73±5% (p<0.0001) and MF1 by 64±6% (p = 0.0002) in a dosage-dependent manner. The combination of MF1 and DC101 enhanced the inhibitory efficacy and resulted in an accumulation of retinal microglia at the CNV lesion. Similarly, both MF1 and DC101 significantly suppressed retinal NV in OIR at 50 mg/kg: DC101 suppressed retinal NV by 54±8% (p = 0.013) and MF1 by 50±7% (p<0.0002). MF1 was even more effective at inhibiting ischemia-induced BRB breakdown than DC101: the retina/lung leakage ratio for MF1 was reduced by 73±24%, p = 0.001 and for DC101 by 12±4%, p = 0.003. The retina/renal leakage ratio for MF1 was reduced by 52±28%, p = 0.009 and for DC101 by 13±4%, p = 0.001.
Conclusion
Our study provides further evidence that both VEGFR1 and 2 mediate pathological angiogenesis and vascular leakage in these models of ocular disease and suggests that antagonist antibodies to these receptor tyrosine kinases (RTKs) are potential therapeutic agents.
doi:10.1371/journal.pone.0021411
PMCID: PMC3120882  PMID: 21731737
17.  Retinopathy of prematurity and risk factors: a prospective cohort study 
BMC Pediatrics  2005;5:18.
Background
Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants.
Methods
Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP.
Results
Of the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725) survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks) had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03). With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age, dependence on ventilation, and use of postnatal steroids were intertwined. Simultaneous presence of these factors seems to indicate severe disease status.
Conclusion
Prolonged and late postnatal steroids treatment in very low birth weight infants may pose an increased risk for the development of severe retinopathy of prematurity; however, use of postnatal steroids may also be a marker for severity of illness. Further studies need to focus on biologic markers in the pathogenesis of retinopathy of prematurity and to better understand the influence of therapies.
doi:10.1186/1471-2431-5-18
PMCID: PMC1175091  PMID: 15985170
18.  FINAL RESULTS OF THE EARLY TREATMENT FOR RETINOPATHY OF PREMATURITY (ETROP) RANDOMIZED TRIAL 
ABSTRACT
Purpose
To present the final results of the Early Treatment for Retinopathy of Prematurity Study.
Methods
Infants with bilateral high-risk prethreshold retinopathy of prematurity (ROP) (n = 317) had one eye randomized to early retinal ablative treatment and the fellow eye managed conventionally (control eye). In asymmetric cases (n = 84), the eye with high-risk prethreshold ROP was randomized to early or to conventional management. High risk was determined using a model based on the Cryotherapy for Retinopathy of Prematurity natural history cohort. The primary outcome was visual acuity assessed by masked testers using the Teller acuity card procedure. Structural examinations were performed at 6 and 9 months.
Results
Grating acuity results showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.8% to 14.3% (P < .005). Unfavorable structural outcomes were reduced from 15.6% to 9.0% (P < .001) at 9 months. Further analysis supported retinal ablative therapy for eyes with type I ROP, defined as zone I, any stage ROP with plus disease; zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 with plus disease. The analysis supported a “wait and watch” approach to type II ROP, defined as zone I, stage 1 and 2 without plus disease, or zone II, stage 3 without plus disease. These eyes should be considered for treatment only if they progress to type I ROP or threshold.
Conclusion
Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes in both primary and secondary (structural) measures.
PMCID: PMC1280104  PMID: 15747762
19.  Oral glucose for pain relief during examination for retinopathy of prematurity: a masked randomized clinical trial 
Clinics  2013;68(2):199-203.
OBJECTIVE:
Ophthalmologic examination for retinopathy of prematurity is a painful procedure. Pharmacological and non-pharmacological interventions have been proposed to reduce pain during eye examinations. This study aims to evaluate the analgesic effect of 25% glucose using a validated pain scale during the first eye examination for retinopathy of prematurity in preterm infants with birth weight ≤1,500 g and/or gestational age ≤32 weeks.
METHODS:
A masked, randomized clinical trial for one dose of 1 ml of oral 25% glucose solution 2 minutes before the first ophthalmologic examination for retinopathy of prematurity was conducted between March 2008 and April 2010. The results were compared to those of a control group that did not receive oral glucose solution. Pain was evaluated using a Neonatal Infant Pain Scale immediately before and immediately after the ophthalmologic examination in both groups. Clinicaltrials.gov: NCT00648687
RESULTS:
One hundred and twenty-four patients who were examined for the first time for retinopathy of prematurity were included. Seventy were included in the intervention group and 54 in the control group. The number of patients with pain immediately before the procedure was similar in both groups. The number of patients with pain after ophthalmologic examination was 15.7% in the intervention group and 68.5% in the control group (p<0.001).
CONCLUSIONS:
One ml of oral 25% glucose solution given 2 minutes before an ophthalmologic examination for retinopathy of prematurity was an effective measure for pain relief.
doi:10.6061/clinics/2013(02)OA13
PMCID: PMC3584268  PMID: 23525316
Premature; Retinopathy of Prematurity; Pain; Pain Measurement; Stress; Neonatal Infant Pain Scale (NIPS)
20.  Differential diagnosis of leukocoria and strabismus, first presenting signs of retinoblastoma 
Leukocoria in infants is always a danger signal as retinoblastoma, a malignant retinal tumor, is responsible for half of the cases in this age group. More common signs should also be considered suspicious until proved otherwise, such as strabismus, the second most frequent sign of retinoblastoma. Less frequent manifestations are inflammatory conditions resistant to treatment, hypopyon, orbital cellulitis, hyphema or heterochromia. Other causal pathologies, including persistent hyperplastic primary vitreous (PHPV), Coats’ disease, ocular toxocariasis or retinopathy of prematurity, may also manifest the same warning signs and require specialized differential diagnosis. Members of the immediate family circle are most likely to notice the first signs, the general practitioner, pediatrician or general ophthalmologist the first to be consulted. On their attitude will depend the final outcome of this vision and life-threatening disease. Early diagnosis is vital.
PMCID: PMC2704541  PMID: 19668520
leukocoria; strabismus; retinoblastoma; Coats’ disease; persistent hyperplastic primary vitreous (PHPV)
21.  Deactivation of the Rod Response in Retinopathy of Prematurity (ROP) 
It is known that retinopathy of prematurity (ROP) alters the activation of rod photoreceptors, but the effect of ROP on deactivation has not been investigated. We studied deactivation using a paired flash procedure in 22 subjects (12 infants and 10 older subjects) with a history of preterm birth and ROP. The amplitude of the rod isolated a-wave response to a flash presented 2 to 120 seconds after a test flash was measured, and the time at which it reached 50% of the single flash amplitude (t50) was determined by linear interpolation. Deactivation results were compared to those in former pre-terms who never had ROP (n=6) and term born controls. In infants, t50 values of ROP subjects did not differ from those in subjects who never had ROP or term born controls. Among mature ROP subjects, eight of 12 had t50 values longer than any control subject. Prolonged deactivation in these mature ROP subjects may indicate lack of maturation of the deactivation process (t50) or progressive compromise of retinal function with increasing age.
doi:10.1007/s10633-010-9228-z
PMCID: PMC2905494  PMID: 20349203
Electroretinogram; Retinopathy of prematurity; Rod photoreceptor; Deactivation
22.  Evaluation of internet websites about retinopathy of prematurity patient education 
Background/aims: The success of the treatment in patients with retinopathy of prematurity (ROP) is mainly associated with timely diagnosis and appropriate management. Information dissemination is crucial for the outcome of ROP. This study aimed to evaluate the quality of the information about ROP available for patients on the internet.
Methods: Cross sectional study. In March 2004 the ROP information available on the internet was evaluated using two search engines (MetaCrawler and MSN) and four key terms (“retinopathy of prematurity,” “premature eye,” “premature retina,” and “ROP”). The quality of each website was evaluated using a score system. The sites were classified as academic, organisational, or commercial. Readability, general quality of the website (based on ownership, purpose, authorship, author qualification, attribution, interactivity, and currency), and quality of the content specific to ROP (definition, causes, epidemiology, risk factors, diagnosis, classification, treatment, and prognosis) were analysed.
Results: Of 114 websites evaluated, 40 were included. 10 sites (25.0%) were academic, eight (20.0%) organisational, and 22 (55.0%) commercial. In the majority of the sites (62.5%) the ROP information was fair or poor.
Conclusions: A large amount of information about ROP is available on the internet. However, most websites were considered incomplete.
doi:10.1136/bjo.2004.055111
PMCID: PMC1772623  PMID: 15834086
internet; retinopathy of prematurity
23.  The prevalence and severity of diabetic retinopathy, associated risk factors and vision loss in patients registered with type 2 diabetes in Luganville, Vanuatu 
Aim
To determine the prevalence and severity of diabetic retinopathy in patients with type 2 diabetes in Luganville, the second largest town in Vanuatu. Additionally, to investigate risk factors for retinopathy and the effect of retinopathy on visual acuity (VA) within this group.
Method
All 83 registered patients with type 2 diabetes in Luganville, a town of 13 121 people, were invited for an interview and anthropometric measurements. A questionnaire including assessment of hypertension and glycaemic control, which are known risk factors for diabetic retinopathy, was administered. This sample accounted for approximately 1.07% of Luganville's adult population. Presenting VA was measured. The retina was photographed with a non‐mydriatic fundus camera and images later independently graded for the extent of retinopathy.
Results
68 (82%) of the 83 patients attended. The mean (SD) age was 54 (11) years and 31 (46%) were male. Diabetic retinopathy was present in 36 (52.9%) of the sample. Sight‐threatening retinopathy requiring urgent referral was present in 15 (22.1%) patients. Presenting VA was worse than 6/12 in the better eye in n = 32 (47%) and in up to half of these cases the principal cause was retinopathy. In addition, four people had uniocular blindness resulting from diabetes. The mean body mass index was lower in those patients with diabetes with retinopathy than in those without (p = 0.010), but there were no other significant differences between the two groups and, specifically, no difference in the frequency of retinopathy risk factors. 42 (61.8%) patients had hypertension (⩾135/85 mm Hg) or were taking antihypertensive therapy.
Conclusions
The prevalence of registered patients with diabetes in Luganville's adult population was 1.07%. Diabetic retinopathy was highly prevalent in the sample (in 36, 52.9%), and in 15 (22.1%) there was a significant threat to sight, with up to 25% of the sample possibly already affected by decreased VA or blindness resulting from diabetes‐related eye disease. Retinopathy risk factors were also prevalent. A diabetes screening programme with baseline ophthalmic assessment and follow‐up are urgently needed to enable timely intervention and treatment.
doi:10.1136/bjo.2006.104174
PMCID: PMC1994739  PMID: 17077115
24.  Antisense Oligonucleotide Therapy in Diabetic Retinopathy 
Diabetic retinopathy is one of the leading causes of blindness in the United States and other parts of the world. Historically, laser photocoagulation and vitrectomy surgery have been used for the treatment of diabetic retinopathy, including diabetic macular edema. Both procedures have proven to be useful under certain conditions but have their limitations. New pathways and processes that promote diabetic retinopathy have been identified, and several new therapeutic approaches are under investigation. These new therapies may be beneficial in the treatment of diabetic retinopathy and include antivascular endothelial growth factor agents, corticosteroids, and therapies that may potentially target a number of additional diabetic retinopathy-related factors and processes, including antisense oligonucleotides. Second-generation antisense oligonucleotides, such as iCo-007, may offer a significant advantage in the treatment of diabetic retinopathy by downregulating the signal pathways of multiple growth factors that seem to play a critical role in the process of ocular angiogenesis and vascular leakage. Benefits of such molecules are expected to include the specificity of the kinase target and an extended half-life, resulting in less frequent intravitreal drug administration, resistance to molecule degradation, and a good safety profile.
PMCID: PMC2769949  PMID: 20144342
antisense oligonucleotides; c-Raf kinase; diabetic macular edema; diabetic retinopathy; iCo-007; multiple proangiogenic factors; neovascular growth; vascular leakage
25.  Onset of retinopathy of prematurity as related to postnatal and postconceptional age. 
The hypothesis that both perinatal events and stage of retinal development are important factors in determining the age at onset of retinopathy of prematurity (ROP) was tested by comparing gestational age at birth with postnatal and postconceptional age when ROP (using ICROP) was first seen. The study population consisted of 207 infants (111 placebo (P) treated, 96 vitamin E (E) treated) who developed ROP among a group of 914 premature infants (460 P, 454 E) enrolled in a randomised clinical trial of the effect of prophylactic use of vitamin E at pharmacological serum levels on incidence and severity of retinopathy. The mean postnatal age at onset of retinopathy was delayed in E treated infants compared with P treated infants by 1.4 weeks (t = 4.004, p < 0.0001). For both P and E treated infants postnatal age at onset of ROP (which reflects the state of retinal development at which birth insults occur) and postconceptional age at onset of ROP which defines state of maturity) were correlated with gestational age at birth. This suggests that both the event of premature birth and the extent of retinal development are important in determining when ROP will first be observed.
PMCID: PMC504257  PMID: 1390510

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